Viral Hepatitis

Medicine Student Lecture

David R Nelson, M.D.

Associate Professor of Medicine
Director, Hepatology and Liver Transplantation
University of Florida

Case 1:
29 y/o female came to your clinic with:
Jaundice, Abdominal pain, Nausea / Vomiting
AST-2,000 ALT- 2,500, Total bili 1.8
She denies IVDA or any recent drug/medicine exposure, but
had unprotected sex about 6 weeks ago
Ultrasound shows normal appearing liver and blood flow
Her diagnosis is

Causes of Acute Hepatitis

Acute Hepatitis

Viral Hepatitis

Drugs

A, B/D, C, E
EBV
CMV & HSV

Ethanol
Tylenol
Halothane

Toxins

Vascular

Jamaica Bush Tea

Mushrooms

Hypotension
Budd-Chiari

Autoimmune
Hepatitis

Metabolic
Wilson's Disease
A1AT

Case:
38 y/o male with past medical history of abnormal ALT for
past 4 years. He had a blood tx as a child due to MVA.
Patient came to your clinic with:
ALT 150, AST 100
HBsAb +, HBcAb +
HCV Ab +
HAV IgG +
What is your dx?

Causes of Chronic Hepatitis

Chronic Hepatitis

Viral Hepatitis
Hep B
Hep C

Drugs
MTX
INH
Amiodarone

Alcohol

NAFLD

Autoimmune
AIH
PBC
PSC

Metabolic
A1AT
HHC
Wilson's

Abbreviations:
NAFLD: nonalcoholic fatty liver disease; AIH: autoimmune hepatitis; PBC: primary biliary cirrhosis
PSC: primary sclerosing cholangitis, A1AT: alpha-1 antitrypsin deficiency, HHC:hereditary hemochromotosis

Acute Viral Hepatitis by Type, USA: 1982-1993

34%
47%

16%
3%

Source: CDC Sentinel Counties Study on Viral Hepatitis

Hepatitis A
Hepatitis B
Hepatitis C
Hepatitis
Non-ABC

Hepatitis A Virus
27 nm

Nucleic Acid: 7.5 kb ssRNA

Transmission route: fecal-oral

Clinical presentation
- Jaundice: Adults- 30%, Children- <5%
- Fulminant: <1%
Diagnostic tests
- Acute infection: IgM anti-HAV
- Chronic infection: Not applicable
Immunity: IgG anti-HAV
Case-fatality rate: 0.1 2.7%
Chronic infection: None

Global Prevalence of Hepatitis A Infection

HAV Prevalence
High
Intermediate
Low
Very Low

Hepatitis A Virus Infection

Typical Serologic Course

Symptoms

Total anti-HAV

Titer

ALT

Fecal
HAV

IgM anti-HAV

Months after Exposure

12

24

Hepatitis A Prevention - Immune Globulin

Preexposure
Travelers to high HAV-prevalence regions
Postexposure (within 14 days)
Routine
Household and other intimate contacts
Selected situations
Institutions (e.g. daycare centers)
Common source exposure (e.g. food prepared
by infected food handler)

Hepatitis A: Pre-exposure Vaccination

Persons at increased risk or danger of infection
Travelers to intermediate and high
HAV prevalence areas
Men having sex with men
Injecting drug users
Persons with chronic liver disease
Communities with high rates of hepatitis A
(e.g., Alaskan Natives, Native-Americans)
Routine pre-school childhood vaccination
ACIP Recommendations MMWR 1999; 48(RR12):1

Hepatitis E Virus

32 nm

Nucleic Acid: 7.5 kb ssRNA

Fecal-oral transmission (human to human)

Contaminated water supplies in tropical
or subtropical developing countries
Mainly young adults
Can infect primates, swine, sheep, rats
Swine may be reservoir of infection in
North America
Maternal-infant transmission occurs and
is often fatal

Hepatitis E

Clinical Characteristics
Similar to hepatitis A
Dx: IgG anti-HEV (seroconversion)
Can cause severe acute hepatitis
Subclinical infection is common
Attenuated virus from animal reservoirs
Low-dose infections often asymptomatic
No chronic infection
Up to 20% mortality among pregnant women (esp. third
trimester)

Hepatitis B Virus
HBsAg

42 nm

HBcAg

HBV DNA

Hepadnaviridae member that primarily infects liver cells

50 to 100 times more infective than HIV
Multiple genotypes exist (A-H)
DNA virus found in blood and body fluids
Able to survive in dried blood for longer than 1 week

> 350 million carriers (HBsAg + > 6 months)

Geographic Distribution of Chronic HBV

Infection

10th cause of death

(1 million / year)

Cirrhosis in 20%
(75 - 100 million)

HCC in 5 - 10%
(20 - 40 million)

HBsAg Prevalence
8% - High
2-7% - Intermediate
<2% - Low

Hepatitis B Prevalence
Overall U.S. prevalence: 0.3%
Asian Americans: ~10-13%

Son D, Asian Am Pac Isl J Health 2001

Slide courtesy of Robert Gish, MD

HBV Sources of Infection

Household, 3%
MSM, 23%
Other, 23%
Sex
contact, 23%

Multiple sex
partners, 24%

IDU, 20%

Many patients do not reveal IDU as source of infection

Centers for Disease Control and Prevention. Hepatitis B.
In: Atkinson W et al, eds. Epidemiology & Prevention of
Vaccine-Preventable Diseases. 8th ed Washington DC:
Public Health Foundation; 2005:191-212.

Signs and Symptoms of Acute Hepatitis B

About 30% of persons have no signs or symptoms
If symptoms are present, generally nonspecific including:

Jaundice
Fatigue
Abdominal Pain
Loss of Appetite

Nausea, vomiting
Joint pain
Dark Urine
Clay-colored bowel
movements

Hepatitis B - Clinical Features

Incubation period

Average: 60 90 days
Range: 45 180 days

Clinical illness (jaundice)

< 5 yrs of age: <10%

5 yrs of age: 30 50%

Acute case-fatality rate

0.5 1%

Chronic infection

< 5 yrs of age: 30 90%

5 yrs of age: 2 10%

Mortality from chronic liver disease

15 25%

Progression to Chronic Hepatitis B Virus

Infection
Typical Serologic Course
Acute
(6 months)

Chronic
(Years)
HBeAg

anti-HBe
HBsAg
Total anti-HBc

Titer

HBV DNA

IgM anti-HBc

8 12 16 20 24 28 32 36

52

Weeks after Exposure

Years

Interpretation of Serologic Markers

Acute
hepatitis B
HBsAg

(may clear)

Anti-HBs

Chronic
HBeAg +
disease

Chronic
HBeAG
disease

Anti-HBc
IgM

Anti-HBc

HBeAg

(may be
only
marker
during
window
period)

Successful
Vaccination

Resistance
to antiviral
agents

(in some
cases)

Anti-HBe

DNA (PCR
if required)

Recovery
from acute
hepatitis B

(sequence
pol region)

Hepatitis B: Disease Progression

Liver Cancer
(HCC)
5%-10% 1
2-6%
Acute
Infection

Chronic
Infection

90% in perinatal
30-90% in children<5yrs old
5% in healthy adults
Higher in HIV, immune suppressed

Cirrhosis
10-30% 1

Liver Failure
(Decompensation)
23% within 5 years

1.
2.
3.
4.

Torresi J et al. Gastroenterology. 2000.

Fattovich G et al. Hepatology. 1995.
Moyer LA et al. Am J Prev Med. 1994.
Perrillo R et al. Hepatology. 2001.

Liver
Transplantation

Death

Chronic HBV is the 6th

leading cause of liver
transplantation in the US4

Targeted Surveillance for HCC

Hepatitis B Carriers

Asian males > age 40

Asian females > age 50
All cirrhotic HBV carriers
Family history of HCC
Africans > age 20
High HBV DNA

Non-hepatitis B Cirrhosis

Hepatitis C
Alcoholic cirrhosis
Genetic hemochromatosis
Primary biliary cirrhosis
Other (? efficacy)
A1AT deficiency
NAFLD
Autoimmune hepatitis

Surveillance for HCC should be with ultrasound at

6 to 12 month intervals; AFP is not adequate

Bruix J and Sherman M. Hepatology 2005;42:1208

Prevention of Transmission of Hepatitis B

Vaccination
1. Vaccinate Sexual and household contacts
2. Newborns of HBV-infected mothers
HBIG and
hepatitis B vaccine at delivery
3. Test for response to vaccination
infants of HBsAg-positive mothers (9 to 15 months )
health care workers,
dialysis patients, and
sexual partners
1-2 months
4. Follow-up testing of vaccine responders
Annually for chronic hemodialysis patients

Goals of Treatment in HBV

Reduce the risk of disease progression
Reduce the risk of hepatocellular carcinoma
Loss of HBeAg, HBeAg HBeAb
Undetectable HBV-DNA
(<105 copies/ml = 20,000IU/mL)
Normalization of ALT
Histologic Response
HBsAg HBsAb

Virologic Response

Approved Treatments

Lok AND McMahon. .Hepatology, Vol. 45, No. 2, 2007

Hepatitis D Virus: Morphology and

Characteristics
Nucleic Acid: 1.7 kb ssRNA
Classification: unclassified,
related to viroids; deltavirus
Transmission: sex, IVDA

35-37nm

Clinical features
- Fulminant: 2 7.5%
- Chronic infection
Superinfection: 80%
Coinfection: < 5%
Diagnostic tests
-Acute infection: IgM anti-HDV
-Chronic infection:IgG anti-HDV, HBsAg +

Modes of HDV infection

Coinfection

D
Superinfection

B
D

HCV Life-Cycle and Pathogenesis

Cell Binding
and Infection

Immune
Recognition

Replication

HCV

Immune
Response

Effector

CD4
CD8
NK
DC

Cytokines

Viral Packaging
and Release

HSC
HSC
Fibrosis
Fibrosis

Course of Acute HCV Infection

1000

HCV RNA positive

Anti-HCV
Symptoms

ALT (IU/L)

800
600
400
200

Normal ALT

6 8 10 12 24 1 2 3 4 5
Weeks
Months
Time After Exposure

Hoofnagle JH. Hepatology. 1997;26:15S. Carithers RL Jr, et al. Semin Liver Dis.
2000;20:159-171. Pawlosky JM. Hepatology. 2002;36(suppl 1):S65-S73. NIH Management
of Hepatitis C Consensus Conference Statement. June 10-12, 2002. Available at:
http://consensus.nih.gov/2002/2002HepatitisC2002116html. Accessed April 10, 2007.

Symptoms, or Lack of, in Chronic

HCV Infection
Symptomatic
37%
Patients (%)

Cirrhosis
7%

100
80
60
40
20
0

56%
Asymptomatic

80

Fatigue

Patients* With HCV infection (%)

ALT Elevations Are Not Indicative of

Chronic HCV Infection
100
80
60
42

43

40
15

20
0
Persistently
Normal ALT

Inglesby TV, et al. Hepatology. 1999;29:590-596.

Intermittently
Elevated ALT

Persistently
Elevated ALT

Diagnostic Tests for HCV Infection

Specifications
Mode of detection
Sensitivity
Specificity
Detection postexposure
Use

Diagnostic Test Type

Serologic
Virologic
Antibodies
Virus
> 95%
> 98%
Variable
> 98%
2-6 mos
2-6 wks
Screening
Confirmation

CDC Morbidity Mortality Weekly Report. 1998;16(RR-19):1-33. NIH Management of

Hepatitis C Consensus Conference Statement. June 10-12, 2002. Available at:
http://consensus.nih.gov/2002/2002HepatitisC2002116html. Accessed April 10, 2007.

Molecular Virologic Assays

Qualitative assays

Quantitative assays

High sensitivity
( 50 IU/mL)

Detection cutoff > qualitative

How much HCV is present?

Is HCV present?

Genotype
assays
What type of HCV is present?

Clinical Significance of HCV Genotypes

Great genetic diversity: 2 genotypes (1 through 6)
Multiple subtypes: a, b, c, etc
Genotype is best pretreatment predictor of response
Genotype 1: least responsive to therapy
Determines dose and duration of therapy
Genotype 1: 48 weeks of peg-IFN alfa + RBV 1000-1200
mg
Genotype 2/3: 24 weeks of peg-IFN alfa + RBV 800 mg
All patients should have genotype determined prior to initiating
therapy
Choo QL, et al. Science. 1989;244:359-62. NIH Consensus Development
Conference Statement. Bethesda, Md: National Institutes of Health;
June 10-12, 2002. Hadziyannis SJ. Ann Intern Med. 2004;140:346-355.

Prevalence of HCV Dependant on Risk Factors

Hemophilia
IVDA
Prison
HIV
Blood transfusion prior to 90
Infants to HCV+ Mothers
Sexual Partner
General Population

Adapted from MMWR.1998;47:5.

74-90%
72-89%
40%
30-40%
5-9%
5%
0.5-3%
1.8%

Prevalence of HCV Infection:

United States
7

Mexican
American
3.5%

Anti-HCV+ (%)

African
American
3.2%

5
4
3

Caucasian
1.1%

2
1
0

611

1219

2029

4049
3039
Age (yr)

Alter et al. N Engl J Med. 1999;341:556-562.

5059

6069

70+

HCV: Disease Progression

Time: 20-30 years

HCV infection
60-85%1

Chronic HCV

Cirrhosis
20%-50%2

Hepatic Failure
~ 20%3

~20%4

Liver Cancer
1. NIH Consensus Development Conference Statement; March 24-26, 1997.
2. Davis GL et al. Gastroenterol Clin North Am. 1994;23:603-613.
3. Koretz RL et al. Ann Intern Med. 1993;119:110-115.
4. Takahashi M et al. Am J Gastroenterol. 1993;88:240-243.

Liver Transplant
Candidates

Histologic Progression of HCV

Monitored by Liver Biopsy
Inflammation Grade
Measure of severity and ongoing disease activity
0-4 (METAVIR)
Inflammation leads to scarring/fibrosis

No fibrosis

Fibrosis Stage
Amount of fibrous scar tissue
0-4 (METAVIR)
Stage 4 = cirrhosis
Indicates long-term disease progression

Brunt EM. Hepatology. 2000;31:241-246.

Cirrhosis

Common Schedule and Type of HCV Testing

Decision to Treat

Identification
Identification
and Planning
and Planning

Treatment

Stage

Diagnosis

Prognosis

Treatment
Duration

Assess Response
and Resistance

Liver biopsy

Genotyping
Quant HCV
RNA

Quant HCV RNA

Assay

Serological
Qual HCV
RNA

Improvements in Therapy of HCV

1998

2001

2002

Sustained Virologic
Response (%)

1991

IFN
6m
Strader DB et al. Hepatology 2004;39:1147-1171

IFN
12m

IFN/RBV
6m

IFN/RBV
12m

Peg-IFN
12m

Peg-IFN/
RBV 12m

Current standard treatment duration is

48 or 24 weeks according to genotype
HCV genotyping
HCV-1 (4,5,6)
Quantitative HCV RNA

HCV-2,3

Peg-IFN+ RBV
1000/1200 mg/day

Peg-IFN +
RBV 800 mg/day
for 24 weeks

Quantitative HCV RNA at week 12

<2 log decline

Stop or re-evaluate
therapy

2 log decline or HCV RNA ()

48 weeks

The Burden of Liver Disease Associated

with HCV is Increasing
An estimated 5 million Americans have been infected with HCV, of whom
4 million are chronically infected
Approximately 30,000 people in the US are infected with hepatitis C each
year
Hepatitis C is the leading causes of liver disease and cirrhosis in US
12,000 - 15,000 people die of hepatitis C each year in the US
The CDC estimate that the number of annual deaths from hepatitis C will
triple in the next 10 - 20 years
The estimated medical and work loss costs per year of hepatitis C is over
$600 million

Source: American Liver Foundation